The major aim of this research is to elucidate cellular and molecular interactions governing the formation of precise sets of connections during mammalian visual system development. Research is centered on how connections between the lateral geniculate nucleus (LGN) and primary visual cortex are established during fetal development and during the postnatal critical period for t he effects of visual experience. Three interrelated specific aims address the central hypothesis that precise adult connections arise as a consequence of circuit readjustment in primary visual cortex driven by dynamic interactions between neural activity and gene expression. 1. To determine the sign of synaptic input from subplate to layer 4. The hypothesis that subplate neurons, along with LGN axons, regulate cortical activity and during the critical period will be addressed. Ablation of subplate neurons prevents formation of ocular dominance columns (ODCs) and alters the expression of genes considered to be key regulators of synaptic plasticity. Experiments will identify and characterize subplate inputs to cortex using electrophysiological, anatomical and calcium imaging approaches. 2. To determine the functional contribution of subplate neurons to formation to formation and maturation of thalamocortical connections. Experiments will acutely or chronically eliminate subplate neurons prematurely, or alter their excitability, to examine the consequences for ensuing development of ODCs and cortical circuits. These manipulations exploit the fact that subplate neurons have distinct physiological and molecular phenotypes that permit their selective inactivation, activation, or removal. 3. To identify sets of genes expressed by cortical neurons and regulated by retinal activity. These experiments address the hypothesis that there is a dynamic and reciprocal relationship between neural activity and the expression of genes required for synaptic readjustments leading to the final patterning of connections. Candidate genes will be identified via unbiased differential screens for activity-regulated genes expressed in visual cortex during the critical period. Preliminary results using cDNA microarrays have identified a set of 50 candidates-both known and novel. Experiments to extend findings, and to test candidate gene function are proposed. Collectively, these experiments should contribute to a framework for constructing a molecular understanding of the critical period in visual system development. Results should also add to knowledge of mechanisms of normal development and learning in children, and to an understanding of causes of developmental and neurological disorders such as Dyslexia, Cerebral Palsy and Autism.
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